IGF-1 Regulates Cyr61 Induced Breast Cancer Cell Proliferation and Invasion

Abstract

BackgroundStudies from our laboratory and others have shown that cysteine-rich 61 (Cyr61) may be involved in tumor proliferation and invasion. In earlier studies, we demonstrated increased insulin-like growth factor-I (IGF-1) is associated with breast tumor formation and poor clinical outcomes. In our current study we have investigated IGF-1 regulation of Cyr61 and whether targeting IGF-1 could inhibit Cyr61 induced tumor growth and proliferation.MethodsSeveral ATCC derived normal and breast cancer cell lines were used in this study: MDA-MB231, BT474, MCF-7, and SKBR3. We also tested cells stably transfected in our laboratory with active Akt1 (pAkt; SKBR3/AA and MCF-7/AA) and dominant negative Akt1 (SKBR3/DN and MCF-7/DN). In addition, we used MCF-7 cells transfected with full length Cyr61 (CYA). Monolayer cultures treated with IGF-1 were analyzed for Cyr61 expression by RT-PCR and immunohistochemical staining. Migration assays and MTT based proliferation assays were used to determine invasive characteristics in response to IGF-1/Cyr61 activation.ResultsCells with activated Akt have increased levels of Cyr61. Conversely, cells with inactive Akt have decreased levels of Cyr61. IGF-1 treatment increased Cyr61 expression significantly and cells with high level of Cyr61 demonstrate increased invasiveness and proliferation. Cyr61 overexpression and activation led to decrease in E-cadherin and decrease in FOXO1. Inhibition of the PI3K and MAPK pathways resulted in significant decrease in invasiveness and proliferation, most notably in the PI3K pathway inhibited cells.ConclusionThe findings of this study show that IGF-1 upregulates Cyr61 primarily through activation of the Akt-PI3K pathway. IGF-1 induced MAPK plays a partial role. Increase in Cyr61 leads to increase in breast cancer cell growth and invasion. Hence, targeting Cyr61 and associated pathways may offer an opportunity to inhibit IGF-1 mediated Cyr61 induced breast cancer growth and invasion.

Cyr61 and YB-1 are novel interacting partners of uPAR and elevate the malignancy of triple-negative breast cancer

“…Furthermore, a significant correlation of Cyr61 with the receptor tyrosine kinases insulin receptor (IR), insulin-like growth factor receptor (IGF1R) and c-Met was shown here. This is in agreement with a previous study showing that Cyr61 expression in MCF7 cells was significantly increased following stimulation with IGF-1 [31]. …”

DDR2–CYR61–MMP1 Signaling Pathway Promotes Bone Erosion in Rheumatoid Arthritis Through Regulating Migration and Invasion of Fibroblast-Like Synoviocytes

“…Among them, cysteine‐rich protein 61 ( CYR61 ) was one of the most highly upregulated mRNAs. CYR61, a member of the CCN‐family, is involved in the adhesion, proliferation, and migration of various tumor cell lines. Recently, a few studies have implicated that elevated CYR61 expression in RA patients promotes the secretion of IL‐1β, IL‐6, and IL‐8 by FLS and regulates FLS proliferation and Th17 cell differentiation .…”

The association between glucose-lowering drug use and mortality among breast cancer patients with type 2 diabetes

“…Metformin may also work through an indirect mechanism by improving insulin sensitivity, thereby reducing insulin levels [26], and decreasing activation of IGF-1 receptors [27]. Deactivation of IGF-1 may inhibit Cyr61, and thereby suppress breast cancer growth and invasion [28]. On the other hand, the observed reduction in breast cancer-specific mortality rates in metformin users could also be due to residual confounding or reflect chance, particularly as the association was most apparent among long-term users of metformin.…”